The goal of this proposal is to test whether reactivating dormant or depressed orexin circuits can reduce endoplasmic reticulum stress (ERS), improve neuroprotection and cognitive performance in mouse models of neurodegeneration. The long-term goal of this work is to identify a novel therapeutic strategy for improving cognition in neurodegenerative diseases such as narcolepsy, Parkinson's disease, Alzheimer's disease, and Huntington's disease. These diseases have differing causes and etiology, but loss of a specific subset of hypothalamic cells, the orexin-containing neurons, occurs in all. Hypothalamic orexin neurons project to the hippocampus, a brain area important to learning and memory. Orexin action in the hippocampus improves cognitive performance and was recently shown to protect against neurodegeneration. Neuroprotective signals are reduced and ERS is activated during neurodegenerative disease, suggestive of a common underlying mechanism. Together, these data suggest reduced orexin signaling in neurodegenerative disease may reduce neuroprotection and increase ERS, causing further neurodegeneration, and cognitive decline. A necessary step in determining whether therapeutic intervention can counter the effect of orexin loss in neurodegenerative disease is to test whether orexin-responsive pathways in the brain can be reactivated. The orexin/ataxin-3 mouse, first developed to study orexin loss in narcolepsy, is a transgenic model in which orexin neurons specifically and gradually decline during development, and cognitive processing deteriorates. Yet our preliminary data show that orexin receptor levels remain intact in young and old mice, and that stimulating these receptors with orexin restores cognition. These novel exciting data provide proof-of- concept that stimulation of orexin pathways, even when orexin neurons are lost, can be used as a strategy to improve cognition. We plan to determine the full potential of this strategy in the orexin ataxin (O/A3) mouse and in the alpha synucleinopathy mouse, a classic model of Parkinson disease. We will examine whether increasing hippocampal orexin tone rescues the cognitive deficit noted in these animals. We also have an established designer drug orexin activation model (DREADD), which is a transgenic mouse in which orexin neurons have been modified to be specifically activated by an otherwise metabolically inert drug. These mice will be crossed with the orexin ataxin and the Parkinson's disease (alpha synucleinopathy) mouse to determine whether stimulating remnant orexin neurons can also rescue dormant orexin-responsive pathways. To gain understanding of the underlying basis for observed cognitive changes resulting from manipulation of orexin pathways, we will measure markers of neuroprotection and ERS in hippocampus. Our overall hypothesis is that orexin promotes neuroprotection and reduces ERS, and that reactivating orexin-responsive pathways will ameliorate neurodegeneration-related cognitive disturbances. To test this, we will determine whether orexin replacement therapy and orexin neuron stimulation improves cognitive performance, markers of neuroprotection and ERS in 1) mice with mild, moderate, and severe orexin neuron loss; and 2) in a classic model of PD. We predict that enhancing orexin tone will improve cognitive performance by improving neuroprotection and decreasing ERS. The results of these studies will determine if orexin rescue is an important strategy in countering cognitive decline, and could ultimately provide a therapeutic pathway to target in neurodegenerative disease.